Microcephaly and Cancer Research Group

Group Leader: Sandra Bell, Lecturer
medsmb@leeds.ac.uk

Research Area

Primary microcephaly (MCPH) is a recessive genetic disorder in which the affected individuals are born with a significantly smaller head size and are mentally retarded. We and co-workers have shown that MCPH1 is involved in DNA repair and regulation of cell cycle checkpoints, particularly the control of entry into mitosis causing premature chromosome condensation (Figure 1). We therefore propose that, while germ line defects in MCPH1 cause microcephaly, somatic defects may cause cancer (Figure 1). We have identified reduced Microcephalin expression in both breast and ovarian cancers which is associated with reduced patient survival (Figure 2). We are studying the biological function of Microcephalin to determine how disruption of its activity causes cancer particularly breast and ovarian.

Microcephaly
Figure 1 Mutations in the MCPH1 gene cause microcephaly (A), premature chromosome condensation (B & C) and cancer.

Currently we are utilizing high throughput screening techniques using small molecule and human genome siRNA libraries to elucidate the function of MCPH1. I am a founding member of the BioScreening Technology Group (BSTG) established to perform high-throughput, high-content siRNA screens which is based in our section.

Microcephaly2

Figure 2 Immunohistochemistry staining of paraffin embedded breast cancer samples. Positive nuclear MCPH1 staining (A), loss of MCPH1 expression (B) and comparison of overall survival based on MCPH1 expression in ductal breast cancer patients (C).

CSMD1 (CUB sushi multiple domain protein 1) is a large gene spanning over 2-Mb of chromosome 8p23 (adjacent to MCPH1), which is deleted in many cancer types. A significant amount of evidence points to CSMD1 playing a role in tumour development. We have previously shown that CSMD1 is an independent prognostic factor in breast cancer and we are currently investigating the function of CSMD1 using in vitro and in vivo models.

Ovarian cancer is characterised by late diagnosis, high recurrence of disease and low survival rate. Consequently women who have undergone surgery for ovarian cancers often have additional chemotherapy to kill residual cancer cells and prevent recurrence. However, relapse often occurs, associated with the development of drug resistance (Figure 3). Ovarian cancer stem like cells (CSC’s) are thought to be one mechanism by which tumours become resistant to chemotherapy. Currently we are to trying to identify ovarian CSCs and to investigate how these cells may play a role in drug resistance allowing novel methods to be developed to both identify and kill CSCs, ultimately leading to improved outcome for ovarian cancer patients.

Microcephaly3
Figure 3 (A) Multidrug resistance often develops in cancer cells due to the increased expression of multi drug resistance proteins (MDR) in the cell membrane which export the chemotherapeutic drugs. (B) Immunofluorescence staining of a multidrug resistance protein (green) in an ovarian cancer cell line.

People

Dr. Sandra Bell - Group Leader, Lecturer
Miss Aeshah Awaji - PhD Student
Miss Camilla Coulson-Gilmer - PhD Student
Dr. Victoria Cookson - Research Fellow
Miss Julie Richardson - PhD Student
Mrs Shivani Shukla - Research Technician

Publications

Brüning-Richardson A, Bond J, Alsiary R, Richardson J, Cairns DA, McCormack L, Hutson R, Burns P, Wilkinson N, Hall G, Morrison EE and Bell SM (2012) NuMA overexpression in epithelial ovarian cancer.  PLosONE 2012; 7(6), e38945.

Richardson J, Shaaban AM, Kamal M, Alisary R, Ellis I, Speirs V, Green A and Bell SM (2011) Microcephalin is a novel prognostic marker in breast cancer associated with BRCA1 inactivation. Breast Cancer Res Treat 127(3): 639-48.

Brüning-Richardson A, Bond J, Alsiary R, Richardson J, Cairns DA, McCormack L, Hutson R, Burns P, Wilkinson N, Hall G, Morrison EE and Bell SM (2011) ASPM and microcephalin expression in ovarian ascites correlates with tumour grade and survival. Br J Cancer 104(10):1602-10.

Higgins J, Midgley C, Bergh A-M, Bell SM, Askham JM, Roberts E, Sharif SM, Bennett C, Glover DM, Woods CG, Morrison EE and Bond J (2010) Human ASPM participates in spindle organisation, cleavage furrow orientation and cytokinesis. BMC Cell Biology 2010 Nov2;11:85.

Kamal M, Shaaban A, Zhang L, Walker C, Gray S, Thakker N, Toomes C, Speirs V & Bell SM (2010) Loss of CSMD1 expression is associated with high tumour grade and poor survival in invasive ductal breast cancer.  Breast Cancer Res Treat 121: 555-63.

Studentships

Competitive fully funded PhD scholarships are available within the Faculty Graduate School.

Self-funded students are always welcomed to apply for cancer based PhD projects using a wide range of cell biology and molecular biology techniques. International students must meet the entry requirements for English. Bench fees are required.

Please email medsmb@leeds.ac.uk for informal enquiries.

Related Links

BioScreening Technology Group (BSTG) http://www.bhrc.ac.uk/initiatives/technology-groups/bioscreening/